Patent application WO 95/00497 published Jan. 5, 1995 under the Patent Cooperation Treaty (PCT) describes compounds which inhibit the enzyme, farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. Oncogenes frequently encode protein components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis. Oncogene expression in cultured cells leads to cellular transformation, characterized by the ability of cells to grow in soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by non-transformed cells. Mutation and/or overexpression of certain oncogenes is frequently associated with human cancer.
To acquire transforming potential, the precursor of the Ras oncoprotein must undergo farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzes this modification, farnesyl protein transferase, have therefore been suggested as anticancer agents for tumors in which Ras contributes to transformation. Mutated, oncogenic forms of Ras are frequently found in many human cancers, most notably in more than 50% of colon and pancreatic carcinomas (Kohl et al., Science, Vol. 260, 1834 to 1837, 1993).
In view of the current interest in inhibitors of farnesyl protein transferase, a welcome contribution to the art would be additional compounds useful for the inhibition of farnesyl protein transferase. Such a contribution is provided by this invention.
Inhibition of farnesyl protein transferase by compounds of this invention has not been reported previously. Thus, this invention provides a method for inhibiting farnesyl protein transferase using compounds of this invention which: (i) potently inhibit farnesyl protein transferase, but not geranylgeranyl protein transferase I, in vitro; (ii) block the phenotypic change induced by a form of transforming Ras which is a farnesyl acceptor but not by a form of transforming Ras engineered to be a geranylgeranyl acceptor; (iii) block intracellular processing of Ras which is a farnesyl acceptor but not of Ras engineered to be a geranylgeranyl acceptor; and (iv) block abnormal cell growth in culture induced by transforming Ras.
This invention provides a method for inhibiting the abnormal growth of cells, including transformed cells, by administering an effective amount of a compound of this invention. Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs.
Compounds of the present invention are represented by Formula 1.0: 
or a pharmaceutically acceptable salt or solvate thereof,
wherein Q is: 
Z represents hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, 
heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, or xe2x80x94CY3Y4 wherein Y3 and Y4 independently represent alkyl and aryl or Y3 and Y4, together with the attached carbon atom (xe2x80x94C), can form a cycloalkyl or a cycloalkenyl ring;
wherein R1, R2, R3, R20, R22, R30 and R32 independently represent hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
R25 can represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl or xe2x80x94OR40 wherein R40 can represent alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
Y represents aryl, heteroaryl, heterocycloalkyl or cycloalkyl,
t is zero, 1, 2 or 3;
w is zero or 1; and
A is nothing, hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, cyano, heteroaryl or heteroarylalkyl.
In another embodiment, the present invention is directed toward a pharmaceutical composition for inhibiting the abnormal growth of cells comprising an effective amount of compound (1.0) in combination with a pharmaceutically acceptable carrier.
In another embodiment, the present invention is directed toward a method for inhibiting the abnormal growth of cells, including transformed cells, comprising administering an effective amount of compound (1.0) to a mammal (e.g., a human) in need of such treatment. Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs, and (4) benign or malignant cells that are activated by mechanisms other than the Ras protein. Without wishing to be bound by theory, it is believed that these compounds may function either through the inhibition of G-protein function, such as ras p21, by blocking G-protein isoprenylation, thus making them useful in the treatment of proliferative diseases such as tumor growth and cancer, or through inhibition of ras farnesyl protein transferase, thus making them useful for their antiproliferative activity against ras transformed cells.
The cells to be inhibited can be tumor cells expressing an activated ras oncogene. For example, the types of cells that may be inhibited include pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells, bladder carcinoma tumor cells, prostate tumor cells, breast tumor cells or colon tumors cells. Also, the inhibition of the abnormal growth of cells by the treatment with compound (1.0) may be by inhibiting ras farnesyl protein transferase. The inhibition may be of tumor cells wherein the Ras protein is activated as a result of oncogenic mutation in genes other than the Ras gene. Alternatively, compounds (1.0) may inhibit tumor cells activated by a protein other than the Ras protein.
This invention also provides a method for inhibiting tumor growth by administering an effective amount of compound (1.0) to a mammal (e.g., a human) in need of such treatment. In particular, this invention provides a method for inhibiting the growth of tumors expressing an activated Ras oncogene by the administration of an effective amount of the above described compounds. Examples of tumors which may be inhibited include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, melanoma, prostate carcinoma and breast carcinoma and epidermal carcinoma.
It is believed that this invention also provides a method for inhibiting proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genesxe2x80x94i.e., the Ras gene itself is not activated by mutation to an oncogenic formxe2x80x94with said inhibition being accomplished by the administration of an effective amount of the N-substituted urea compounds (1.0) described herein, to a mammal (e.g., a human) in need of such treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes (e.g., neu, src, abl, lck, and fyn), may be inhibited by the N-substituted urea compounds (1.0).
In another embodiment, the present invention is directed toward a method for inhibiting ras farnesyl protein transferase and the farnesylation of the oncogene protein Ras by administering an effective amount of compound (1.0) to mammals, especially humans. The administration of the compounds of this invention to patients, to inhibit farnesyl protein transferase, is useful in the treatment of the cancers described above.
As used herein, the following terms are used as defined below unless otherwise indicated:
BOCxe2x80x94represents tert-butoxycarbonyl;
BOC-ONxe2x80x94represents [2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile];
Cxe2x80x94represents carbon;
CBZxe2x80x94represents benzyloxycarbonyl;
ClCO2Etxe2x80x94ethyl chloroformate;
CPh3xe2x80x94represents triphenylmethyl;
cycloalkyl-represents a saturated carbocyclic ring, branched or unbranched, of from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms;
DBUxe2x80x94represents 1,8-diazabicyclo[5.4.0]undec-7-ene;
DCCxe2x80x94represents dicyclohexylcarbodiimide;
DCMxe2x80x94represents dichloromethane;
DICxe2x80x94represents diisopropylcarbodiimide;
DIPEAxe2x80x94diiosopropyl ethylamine
DMAPxe2x80x94represents 4-dimethylaminopyridine;
DMFxe2x80x94represents N,N-dimethylformamide;
EDC (also DEC)xe2x80x94represents 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride;
EtOAcxe2x80x94ethyl acetate;
EtOHxe2x80x94ethanol;
Et3Nxe2x80x94triethylamine;
FMOCxe2x80x94represents 9-fluorenylmethyoxycarbonyl;
FMOC-Clxe2x80x94represents 9-fluoroenylmethyl chloroformate;
HATUxe2x80x94represents [O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate];
HOAc or AcOHxe2x80x94acetic acid;
HOBTxe2x80x94hydroxybenzotriazole;
Lutidinexe2x80x942,6-lutidine;
MCPBAxe2x80x94represents m-chloroperbenzoic acid;
Mexe2x80x94methyl;
MeOHxe2x80x94methanol;
NaBH5CNxe2x80x94sodium cyano borohydride
Phxe2x80x94represents phenyl;
TBAFxe2x80x94represents tetrabutylammonium fluoride;
TFAxe2x80x94represents trifluoroacetic acid;
TFAAxe2x80x94trifluoroacetic anhydride;
THFxe2x80x94represents tetrahydrofuran;
M+-represents the molecular ion of the molecule in the mass spectrum;
MH+-represents the molecular ion plus hydrogen of the molecule in the mass spectrum;
Bu-represents butyl;
Etxe2x80x94represents ethyl;
Mexe2x80x94represents methyl;
Phxe2x80x94represents phenyl;
benzotriazol-1-yloxy represents 
1-methyl-tetrazol-5-ylthio represents 
alkyl-(including the alkyl portions of alkoxy, alkylamino and dialkylamino)-represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to ten carbon atoms, also preferably one to six carbon atoms; for example methyl, ethyl, propyl, iso-propyl, n-butyl, t-butyl, n-pentyl, isopentyl, hexyl, isononyl and the like; wherein said alkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano (xe2x80x94CN), xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 can independently represent hydrogen, alkyl, alkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
alkenyl-represents straight and branched carbon chains having at least one carbon to carbon double bond and containing from 2 to 12 carbon atoms, preferably from 2 to 6 carbon atoms and most preferably from 3 to 6 carbon atoms; wherein said alkenyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, alkoxy, amino, alkylamino, cyano (xe2x80x94CN), xe2x80x94CF3, dialkylamino, hydroxy, oxy, phenoxy, xe2x80x94OCF3, heterocycloalkyl, xe2x80x94SO2NH2, xe2x80x94NHSO2R10, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10, xe2x80x94NCOR10 or xe2x80x94COOR10;
alkoxy-an alkyl moiety of one to 20 carbon atoms covalently bonded to an adjacent structural element through an oxygen atom, for example, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and the like; wherein said alkoxy group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano (xe2x80x94CN), xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove;
aryl (including the aryl portion of arylalkyl)xe2x80x94represents a carbocyclic group of 6 to 15 carbon atoms containing one or two aromatic rings (e.g., aryl is phenyl); wherein optionally, said aryl group can be fused with one other aryl, cycloalkyl, heteroaryl or heterocycloalkyl ring provided that when the moiety xe2x80x9cZxe2x80x9d in compound (1.0) is aryl, the fused aryl is a bicyclic ring (e.g napthalene) which is not a tricyclic or greater fused ring system; and wherein any of the available substitutable carbon and nitrogen atoms in said aromatic rings and/or said fused rings may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano (xe2x80x94CN), xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove;
arylalkylxe2x80x94represents an alkyl group, as defined above, wherein one or more hydrogen atoms of the alkyl moiety have been substituted with one or more aryl groups, as defined above (e.g. arylalkyl is benzyl or phenylethyl); wherein optionally, said arylalkyl group can be fused with one other aryl, cycloalkyl, heteroaryl or heterocycloalkyl ring provided that when the moiety xe2x80x9cZxe2x80x9d in compound (1.0) is arylalkyl, the fused arylalkyl is a bicyclic ring (e.g napthalenyl) which is not a tricyclic or greater fused ring system; wherein said arylalkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano (xe2x80x94CN), xe2x80x94CF3, oxy (xe2x95x90O), xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove;
cycloalkyl-represents saturated carbocyclic rings branched or unbranched of from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms (e.g. cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like); wherein said cycloalkyl ring optionally can be fused with one other cycloalkyl, cycloalkenyl or heterocycloalkyl ring to form a bicyclic ring which is not a tricyclic or greater fused ring system; wherein any of the available substitutable carbon and nitrogen atoms in said cycloalkyl ring and/or said fused ring may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano (xe2x80x94CN), xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove;
cycloalkylalkylxe2x80x94represents an alkyl group, as defined above, wherein one or more hydrogen atoms of the alkyl moiety have been substituted with one or more cycloalkyl rings as defined above; wherein said cycloalkylalkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano (xe2x80x94CN), xe2x80x94CF3, oxy (xe2x95x90O), xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove;
cycloalkenylxe2x80x94represents a carbocyclic ring having one or two unsaturated bonds (i.e. carbon to carbon double bonds) and containing from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms wherein said one or two unsaturated bonds do not impart aromatic character to the cycloalkenyl ring; wherein said cycloalkenyl ring optionally can be fused with one other cycloalkyl, cycloalkenyl or heterocycloalkyl ring to form a bicyclic ring (e.g. norbornenyl) which is not a tricyclic or greater fused ring system; wherein any of the available substitutable carbon and nitrogen atoms in said cycloalkenyl ring and/or said fused ring may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano (xe2x80x94CN), xe2x80x94CF3, oxy (xe2x95x90O), xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove;
cycloalkenylalkylxe2x80x94represents an alkyl group, as defined above, wherein one or more hydrogen atoms of the alkyl moiety have been substituted with one or more cycloalkenyl rings as defined above; wherein said cycloalkenylalkyl group optionally can be fused with one other cycloalkyl, cycloalkenyl or heterocycloalkyl ring to form a bicyclic ring (e.g. norbornylmethyl); wherein any of the available substitutable carbon and nitrogen atoms in said cycloalkenylalkyl group and/or said fused ring may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano (xe2x80x94CN), xe2x80x94CF3, oxy (xe2x95x90O), xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 areas defined hereinabove;
halo-represents fluoro, chloro, bromo and iodo;
heteroalkyl-represents straight and branched carbon chains containing from one to twenty carbon atoms, preferably one to six carbon atoms interrupted by 1 to 3 heteroatoms selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94Nxe2x80x94; wherein any of the available substitutable carbon and nitrogen atoms in said heteroalkyl chain may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano (xe2x80x94CN), xe2x80x94CF3, oxy (xe2x95x90O), xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove;
heteroaryl-represents cyclic groups having at least one heteroatom selected from O, S and N, said heteroatom(s) interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic groups containing from 2 to 14 carbon atoms (e.g. heteroaryl is imidazoyl); wherein said heteroaryl group optionally can be fused with one aryl, cycloalkyl, heteroaryl or heterocycloalkyl ring to form a bicyclic ring which is not a tricyclic or greater fused ring system; and wherein any of the available substitutable carbon or nitrogen atoms in said heteroaryl group and/or said fused ring may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, arylalkyl, cycloalkyl, cyano (xe2x80x94CN), xe2x80x94CF3, oxy (xe2x95x90O), xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove. Representative heteroaryl groups can include, for example, furanyl, imidazoyl, pyrimidinyl, triazolyl, 2-, 3- or 4-pyridyl or 2-, 3- or 4-pyridyl N-oxide wherein pyridyl N-oxide can be represented as: 
heteroarylalkylxe2x80x94represents an alkyl group, as defined above, wherein one or more hydrogen atoms have been replaced by one or more heteroaryl groups; wherein said heteroaryl group optionally can be fused with one aryl, cycloalkyl, heteroaryl or heterocycloalkyl ring to form a bicyclic ring which is not a tricyclic or greater fused ring system; and wherein any of the available substitutable carbon or nitrogen atoms in said heteroaryl group and/or said fused ring may be optionally and independently substituted with one, two, three or more of the following: wherein said heteroarylalkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano (xe2x80x94CN), xe2x80x94CF3, oxy (xe2x95x90O), xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94CH2NR12COR10, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove;
heterocycloalkyl-represents a saturated, branched or unbranched carbocylic ring containing from 3 to 15 carbon atoms, preferably from 4 to 6 carbon atoms, which carbocyclic ring is interrupted by 1 to 3 heteroatoms selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94Nxe2x80x94, wherein optionally, said ring may contain one or two unsaturated bonds which do not impart aromatic character to the ring; wherein said heterocycloalkyl group optionally can be fused with one aryl, cycloalkyl, heteroaryl or heterocycloalkyl ring to form a bicyclic ring which is not a tricyclic or greater fused ring system; and wherein any of the available substitutable carbon or nitrogen atoms in said heterocycloalkyl group and/or said fused ring may be optionally and independently and wherein any of the available substitutable carbon and nitrogen atoms in the ring may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano (xe2x80x94CN), xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove. Representative heterocycloalkyl groups can include 2- or 3-tetrahydrofuranyl, 2- or 3- tetrahydrothienyl, 1-, 2-, 3- or 4-piperidinyl, 2- or 3-
pyrrolidinyl, 1-, 2- or 3-piperizinyl, 2- or 4-dioxanyl, morpholinyl, 
or
wherein R10 is defined hereinbefore and t is 0, 1 or 2.
heterocycloalkalkylxe2x80x94represents an alkyl group, as defined above, wherein one or more hydrogen atoms have been replaced by one or more heterocycloalkyl groups; wherein optionally, said ring may contain one or two unsaturated bonds which do not impart aromatic character to the ring; and wherein said heterocycloalkylalkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano (xe2x80x94CN), xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove.
Certain compounds of the invention may exist in different stereoisomeric forms (e.g., enantiomers, diastereoisomers and atropisomers). The invention contemplates all such stereoisomers both in pure form and in mixture, including racemic mixtures.
Certain compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
Certain basic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, the pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention.
All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purpopses of the invention. 
Compounds of the present invention can be prepared according to the following Schemes.
Library Preparation. A library of compounds is prepared by parallel synthesis. A generic structure of these compounds is shown in FIG. 1. The xe2x80x9cAxe2x80x9d group on the side chain histamine along with xe2x80x9cZxe2x80x9d group on N-4 of the piperazine are varied in the library. Every member of the library contains methyl sulfonate at position N-1 of the piperazine core (FIG. 1). 
Referring to Scheme A, the side chain amines 2 were prepared by treating bis-Boc histamine 1 with the corresponding triflate, and subsequent removal of the Boc group. Library was prepared on TentaGel(copyright) (trademark of Rapp Inc., Germany) resin 3 functionalized with 4-(4-formyl-3-methoxyphenoxy)butyric acid 4 (shown in Scheme 1) to give functionalized resin 5. TentaGel resin is a composite of low-cross-linked polystrrene and polyethylene glycol, which has been terminally amino functionalized. Synthesis was initiated in Merrifield shaker vessels with reductive amination of the side chain amines 2 using the aldehyde of the acid cleavable linker of the functionalized resin 5 to give 6. This was followed by coupling N-4-Fmoc N-1-Boc piperazine carboxylic acid 7 with 6 to give 8. Removal of the Fmoc group of 8 gives 9. Resin 9 was dried and loaded into Robbins FlexChem block (96 wells) and subsequent reactions were performed in the block. Resin 9 was reductively alkylated with a number of corresponding aldehydes with NaBH3CN in 2% HOAc in DMF or acylated with corresponding acid chlorides with lutidine in CH2Cl2or sulfonyl chlorides with lutidine in CH2Cl2, or treated with isocyanates and DIPEA in CH2Cl2. Treatment of resin 10 with 10% HCl/MeOH followed by methanesulfonyl chloride gives resin 11. The product 12 is cleaved from resin 1 using trifluoroacetic acid. 
Preparation Procedure for PS 461400 (Scheme 2)
1. Preparation of compound 2. To a stirred solution of triflic anhydride (1.9 mL, 11.3 mmole) in CH2Cl2 (35 mL) under Ar at xe2x88x9275xc2x0 C. was added a solution of 4-cyanobenzyl alcohol (1)(1.37 g, 10.3 mmole) and diisopropylethylamine (1.97 mL, 11.3 mmole) in CH2Cl2 (12 mL) dropwise. Stirring at xe2x88x9278xc2x0 C. was continued for 20 min. and a solution of N-Bis-Boc-histamine (3.2 g, 10.3 mmole) in CH2Cl2 (35 mL) was added. The reaction was allowed to warm to room temperature slowly and stirred overnight. The reaction mixture was washed with sat. Na2CO3 solution (30 mL). The organic phase was dried (Na2SO4) and solvent removed in vacuo. The residue was purified by column chromatography with 5 % MeOH in CH2Cl2 to give 1.38 g product in 41% yield. MS: m/z 327 (MH+). This compound was treated with 25% trifluoroacetic acid in CH2Cl2 (20 mL) for 1 h. Solvent was removed in vacuo. The residue was dissolved in 5% HCl (15 mL) and washed with CH2Cl2 (10 mLxc3x972). The aqueous layer was basified with NaOH to PH=9 and extracted with ethyl acetate (30 mLxc3x974). The combined organic phase was dried (Na2SO4) and solvent removed in vacuo to give 600 mg desired amine 2 in 66% yield. MS: m/z 227 (MH+).
2. Preparation of compound 3. To a stirred solution of the amine (2) (600 mg, 2.65 mmole) and N-4-Fmocxe2x80x94N-1-Boc-piperazine carboxylic acid (1 g, 2.21 mmole) in CH2Cl2 (20 mL) was added DCC (547 mg, 2.65 mmole) and HOBt (358 mg, 2.65 mmole). The reaction was stirred overnight. The reaction mixture was filtered. The filtrate was washed with water (20 mL). The organic phase was dried (Na2SO4) and solvent removed in vacuo. The residue was purified by flash column chromatography with 5% MeOH in CH2Cl2 to give the amide. The amide was treated with 20% piperidine in CHCl3 (10 mL) for 2 h. Solvent was removed in vacuo. The residue was purified by column chromatography with 5-10% MeOH in CH2Cl2 to give 713 mg desired amine in 74% yield. MS: m/z 439 (MH+).
3. Preparation of compound 4. Amine 3 (40 mg, 0.09 mmole) was dissolved in MeOH (3 mL), cyclohexylacetaldehyde (23 xcexcL, 0.18 mmole) and sodium cyanoborohydride (182 xcexcL 1.0 M solution in THF, 0.18 mmole) was added. The reaction was stirred overnight. Solvent was removed in vacuo and the residue was purified by flash column chromatography with 3-5% MeOH in CH2Cl2 to give 22 mg of desired product in 44% yield. MS: m/z 549 (MH+).
4. Preparation of PS461400. To a stirred solution of compound 4 (22 mg, 0.04 mmole) in CH2Cl2 (2 mL) was added trifluoroacetic acid (0.5 mL). The mixture was stirred for 1 h and solvent was removed in vacuo. The residue was pumped on a high vacuum line for 2 h and dissolved in CH2Cl2 (2 mL). To this solution was added diisopropylethyl amine (35 xcexcL, 0.2 mmole) and the cyclohexyl isocyanate (28.5 xcexcL, 0.2 mmole). The reaction was stirred overnight, dissolved in water (10 mL) and extracted with CH2Cl2 (15 mLxc3x972). The organic layer was dried (Na2SO4) and solvent was removed in vacuo. The residue was purified by flash column chromatography with 4% MeOH in CH2Cl2 to give 11 mg desired product in 48% yield. MS: m/z 574 (MH+).
Using substantially the same reaction scheme of the above example, with appropriate alcohol 1, the following compounds were prepared:

Preparation Procedure for PS 321542 (Scheme 3)
1. Preparation of compound 3. To a stirred solution of the anhydride 1 (100 mg, 0.39 mmole) in CH2Cl2 (4 mL) was added a solution of the amine i (105 mg, 0.39 mmole) in a mixture of MeOH/CH2Cl2(0.5 mL/2 mL). The reaction was stirred for 1 h. The reaction was cooled to 0xc2x0 C. and cyclohexyl isocyanate (111 xcexcL, 0.78 mmole) was added. The reaction was stirred overnight. The reaction was partitioned between CH2Cl2 (40 mL) and sat. NaCl solution (20 mL). The organic layer was dried (Na2SO4) and solvent removed in vacuo to give 200 mg desired product in 85% yield. MS: m/z 607 (MH+).
2. Preparation of compound PS321542. To a stirred solution of compound 3 (137 mg, 0.226 mmole) in CH2Cl2 (3 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred for 1 h and solvent was removed in vacuo. The residue partitioned between 1 N NaOH (20 mL) and CH2Cl2 (20 mL). The aqueous layer was extracted with CH2Cl2 and EtOAc. The combined organic phase was dried (Na2SO4) and solvent was removed in vacuo. The amine was dissolved in MeOH (3 mL). To this solution was added cyclohexyl acetaldehyde (57 mg, 0.45 mmole) and sodium cyanoborohydride (1.0 M solution in THF, 452 xcexcL, 0.45 mmole). The reaction was stirred overnight. Solvent was removed in vacuo and the residue partitioned between 1 N NaOH (20 mL) and CH2Cl2 (20 mL). The organic layer was dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography with 4% MeOH in CH2Cl2 to give 52 mg product in 37% yield. MS: m/z 617 (M+).
Using substantially the same reaction scheme of the above example, with racemic anhydride 2 when appropriate, the following compounds were prepared:

Preparation Procedure for 1-(2-Aminoethyl)-5-benzylimidazole (10) and 1-(2-Aminoethyl)-4-benzylimidazole (12) (Scheme 4)
1. Preparation of compound 2. To a stirred solution of imidazole (5g, 73.4 mmole) in CH2Cl2 (30 mL) at 0xc2x0 C. was added triethylamine (15.4 mL, 110 mmole) and dimethylsulfamoyl chloride (8.3 mL, 77.1 mmole) dropwise. The reaction was allowed to warm to room temperature slowly and stirred overnight. The reaction was quenched with water (30 mL) and extracted with CH2Cl2 (30 mLxc3x972). The organic phase was dried (Na2SO4) and solvent removed in vacuo to give compound 2 in 89% yield. MS: m/z 176 (MH+).
2. Preparation of compound 5. To a stirred solution of compound 2 (1.0 g, 5.72 mmole) in THF (20 mL) at xe2x88x9278xc2x0 C. under Ar was added n-BuLi in hexane (2.5 M solution, 2.44 mL, 6.12 mmole). The reaction mixture was stirred at at xe2x88x9278xc2x0 C. for 30 min., and chlorotriethylsilane (1.92 mL, 11.44 mmole) was added. The reaction was stirred at room temperature for 5 h, then solvent and excess chlorosilane was removed under reduced pressure by gentle heating to give intermediate 3. THF (20 mL) was added to intermediate 3 and the solution was cooled to xe2x88x9278xc2x0 C. Sec-butyllithium in cyclohexane (1.3 M solution, 8.8 mL, 11.44 mmole) was added and the mixture stirred at xe2x88x9278xc2x0 C. for 30 min., then benzyl bromide (2.04 mL, 17.16 mmole) was added. Stirring was continued at xe2x88x9278xc2x0 C. for 30 min., and at room temperature overnight. Solvent was removed in vacuo to give intermediate 4. Intermediate 4 was stirred with 2 N HCl (50 mL) for 3 h and the mixture was washed with ether (20 mLxc3x972). The aqueous phase was basified with NaOH (40% w/w) to pH=11, then extracted with ether (50 mLxc3x973). Combined organic phase was dried (Na2SO4) and solvent removed in vacuo. The residue was purified by flash column chromatography with 35% hexane in EtOAc to give 560 mg compound 5 in 37% yield. MS: m/z 266 (MH+).
3. Preparation of compound 6. Compound 5 (560 mg, 2.11 mmole) was refluxed in 4% NaOH (w/w, 100 mL) overnight. Solvent was removed in vacuo. The residue was triturated with THF, filtered and dried (Na2SO4). Solvent was removed under reduced pressure to give 240 mg 4(5)-benzylimidazole (6) in 72% yield. MS: m/z 159 (MH+).
4. Preparation of 1-(2-Aminoethyl)-5-benzylimidazole (10). To a stirred solution of compound 6 (230 mg, 1.45 mmole) in H2O/dioxane (1:1, 20 mL) was added sodium carbonate (31 mg, 0.29 mmole) and di-t-butyl-dicarbonate (400 mg, 1.74 mmole). The mixture was stirred overnight, then extracted with CH2Cl2 (40 mLxc3x972). Combined organic layer was washed with water (20 mL), dried (Na2SO4) and solvent was removed in vacuo to give 305 mg compound 7 in 82% yield. MS: m/z 259 (MH+). To a stirred solution of triflic anhydride (219 xcexcL, 1.3 mmole) in CH2Cl2 (5 mL) under Ar at xe2x88x9278xc2x0 C. was added a solution of compound 8 (249 mg, 1.3 mmole) and DIEA in CH2Cl2 (5 mL). Stirring at xe2x88x9278xc2x0 C. was continued for 20 min., a solution of compound 7 in CH2Cl2 (5 mL) was added dropwise. The reaction was allowed to gradually warm to room temperature overnight. To the reaction was added sat. NaHCO3 (10 mL). The mixture was extracted with CH2Cl2 (20 mLxc3x972). Organic layer was washed with water (10 mL), dried (Na2SO4) and solvent removed in vacuo. The residue was purified by column chromatography with 1-5 % MeOH in CH2Cl2 to give 60 mg compound 9. MS: m/z 332 (MH+). Compound 9 was dissolved in MeOH (2 mL) and hydrazine (10 xcexcL) was added. The reaction was stirred overnight and solvent was removed in vacuo. The residue was dissolved in 0.1 N HCl (10 mL) and washed with EtOAc (10 mL). The aqueous phase was basified with NaOH until pH=11, and extracted with EtOAc (20 mLxc3x973). Combined organic layer was dried (Na2SO4) and solvent removed in vacuo to give the title compound 10. MS: m/z 202 (MH+).
5. Preparation of 1-(2-Aminoethyl)-4-benzylimidazole (12). To a stirred solution of triflic anhydride (245 xcexcL, 1.46 mmole) in CH2Cl2 (5 mL) under Ar at xe2x88x9278xc2x0 C. was added a solution of compound 8 (278 xcexcg, 1.46 mmole) and DIEA in CH2Cl2 (5 mL). Stirring at xe2x88x9278xc2x0 C. was continued for 20 min., a solution of compound 6 in CH2Cl2 (5 mL) was added dropwise. The reaction was allowed to gradually warm to room temperature overnight. To the reaction was added sat. NaHCO3 (10 mL). The mixture was extracted with CH2Cl2 (20 mLxc3x972). Organic layer was washed with water (10 mL), dried (Na2SO4) and solvent removed in vacuo. The residue was purified by column chromatography with 1-5% MeOH in CH2Cl2 to give 112 mg compound 11. MS: m/z 332 (MH+). Compound 11 was dissolved in MeOH (2 mL) and hydrazine (10 xcexcL) was added. The reaction was stirred overnight and solvent was removed in vacuo. The residue was dissolved in 0.1 N HCl (10 mL) and washed with EtOAc (10 mL). The aqueous phase was basified with NaOH until pH=11, and extracted with EtOAc (20 mLxc3x973). Combined organic layer was dried (Na2SO4) and solvent removed in vacuo to give the title compound 12. MS: m/z 202 (MH+).
Compound 10 was used to prepare PS319448 using procedure described in scheme 2. Compound 12 was used to prepare PS204446 using procedure described in scheme 2.
Reagents and reaction conditions for protecting and deprotecting compounds is well known, as described, for example, in T. W. Greene and P. Wuts, Protective Groups in Organic Synthesis, 2nd Ed., Wiley Interscience, N.Y. 1991, 473 pages.
Compounds of the present invention and preparative starting materials therof, are exemplified by the following examples, which should not be construed as limiting the scope of the disclosure. Alternative mechanistic pathways and analogous structures within the scope of the invention may be apparent to those skilled in the art, such as by the methods described in WO95/10516.
Compounds of formula (1.0) can be isolated from the reaction mixture using conventional procedures, such as, for example, extraction of the reaction mixture from water with organic solvents, evaporation of the organic solvents, followed by chromatography on silica gel or other suitable chromatographic media. Alternatively, compounds (1.0) can be dissolved in a water-miscible solvent, such as methanol, the methanol solution is added to water to precipitate the compound, and the precipitate is isolated by filtration or centrifugation.
Compounds of the present invention and preparative starting materials thereof, are exemplified by the following examples, which should not be construed as limiting the scope of the disclosure.